To better understand the pharmacologic underpinnings of human memory, we have pursued a "pharmacologic challenge" strategy which involves attempts to model the memory of Alzheimer's disease (AD) in older volunteers (protocol 83-M-0123). After testing numerous medications, we have discovered that a combination of the nicotinic antagonist, mecamylamine, with the central muscarinic antagonist, scopolamine, has proved most effective in briefly modeling the memory impairment of AD. This data is consistent with previously published brain imaging literature, and once more emphasizes the central importance of the cholinergic system in human memory. We are also focusing on the testing of subjects "at risk" for developing AD on the basis of family history and age (protocol 95-M-0096). As part of this study, we are looking for evidence of increased sensitivity to cholinergic blockade in these subjects, even before they manifest signs of cognitive decline. It is our hypothesis that this test might serve as a early diagnostic marker for the disease process. In addition, we are treating AD patients chronically with the anticholinergic scopolamine to determine if they are capable of cholinergic upregulation and increased response to cholinesterase inhibitors (protocol 95-M-0096). This study could have an immediate impact on treatment strategies with AD.